p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model.
p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model.
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DOI：
10.1158/0008-5472.can-12-2246
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发表时间：
2012-11-15
期刊：
影响因子：
11.2
通讯作者：
Chernoff J
中科院分区：
文献类型：
--
作者：
Chow HY;Jubb AM;Koch JN;Jaffer ZM;Stepanova D;Campbell DA;Duron SG;O'Farrell M;Cai KQ;Klein-Szanto AJ;Gutkind JS;Hoeflich KP;Chernoff J
RAS基因是人类癌症中最常见的突变癌基因，并且呈现出特定的治疗困境，因为通过小分子直接靶向Ras蛋白已被证明是困难的。Ras下游的信号传导途径，特别是Raf/Mek/Erk和PI 3 K/Akt/mTOR，由脂质和蛋白激酶主导，这些激酶在Ras驱动的肿瘤中提供了有吸引力的替代靶标。由于p21激活激酶1（Pak 1）已被证明可以调节这两种信号通路，并且本身在许多人类癌症中上调，因此我们评估了Pak 1在Ras驱动的皮肤癌中的作用。在人类鳞状细胞癌（SCC）中，我们发现晚期和分级与PAK 1表达呈强正相关。使用Kras驱动的SCC小鼠模型，我们发现小鼠Pak 1基因的缺失导致肿瘤发生和进展明显减少，伴随着Erk和Akt活性的几乎完全丧失。用两种不同的小分子Pak抑制剂（PF 03758309和FRAX 597）中的任一种治疗KrasG 12 D小鼠，导致肿瘤消退和Erk和Akt活性丧失。在用特异性Mek抑制剂治疗的小鼠中也观察到肿瘤消退，但用Akt抑制剂治疗的小鼠没有。这些发现确立了Pak 1作为KRAS驱动的肿瘤中的新靶点，并表明通过Erk而不是Akt信号通路的作用机制。
The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream of Ras, in particular Raf/Mek/Erk and PI3K/Akt/mTOR, are dominated by lipid and protein kinases that provide attractive alternate targets in Ras-driven tumors. As p21-activated kinase 1 (Pak1) has been shown to regulate both these signaling pathways and is itself upregulated in many human cancers, we assessed the role of Pak1 in Ras-driven skin cancer. In human squamous cell carcinoma (SCC), we found a strong positive correlation between advanced stage and grade and PAK1 expression. Using a mouse model of Kras-driven SCC, we showed that deletion of the mouse Pak1 gene led to markedly decreased tumorigenesis and progression, accompanied by near total loss of Erk and Akt activity. Treatment of KrasG12D mice with either of two distinct small molecule Pak inhibitors (PF03758309 and FRAX597) caused tumor regression and loss of Erk and Akt activity. Tumor regression was also seen in mice treated with a specific Mek inhibitor, but not with an Akt inhibitor. These findings establish Pak1 as a new target in KRAS-driven tumors and suggest a mechanism of action through the Erk, but not the Akt, signaling pathway.